(S,R,S)-AHPC-CO-PEG4-COOH

Background Introduction

(S,R,S)-AHPC-CO-PEG4-COOH is a specialized E3 ligase ligand-linker conjugate commonly utilized in the design of PROTACs (Proteolysis Targeting Chimeras). This compound incorporates the high-affinity AHPC ligand, which targets the Von Hippel-Lindau (VHL) E3 ubiquitin ligase, and features a hydrophilic PEG4 spacer terminating in a carboxylic acid functional group. Its structure is optimally suited for enhancing PROTAC development, enabling targeted protein degradation in medicinal chemistry and chemical biology research.

Mechanism

(S,R,S)-AHPC-CO-PEG4-COOH functions as a bifunctional molecular module in PROTAC design. The AHPC moiety selectively binds to the VHL E3 ubiquitin ligase, while the PEG4 linker offers structural flexibility and improved solubility. The C-terminal carboxylic acid acts as a reactive handle, allowing for efficient conjugation to target protein ligands via robust coupling techniques. Once incorporated into a PROTAC, this conjugate brings the VHL ligase into proximity with a disease-relevant target protein, triggering ubiquitination and proteasomal degradation of the target protein.

Applications

(S,R,S)-AHPC-CO-PEG4-COOH is primarily used as a key intermediate in the synthesis of VHL-based PROTAC molecules, facilitating the development of next-generation drugs that induce selective protein degradation. Its extended PEG4 linker enhances pharmacokinetic properties and cellular permeability. Researchers leverage this conjugate for the discovery and optimization of chemical probes and therapeutics across oncology, neurodegenerative diseases, and immune disorders by enabling rapid prototyping and customization of PROTACs targeting diverse pathogenic proteins.

(S,R,S)-AHPC-CO-PEG4-COOH is a versatile E3 Ligase Ligand-Linker Conjugate utilized in the development of PROTACs for targeted protein degradation. It offers a balanced combination of stability, flexibility, and efficient conjugation potential, making it an ideal choice for academic research. The following provides a detailed description of this molecule.

Linker: The linker in this molecule is a PEG4 chain, which provides a moderate length and flexibility, allowing for optimal spatial orientation between the ligand and the target protein. Its non-cleavable nature ensures stability during cellular processes, enhancing the efficacy of PROTACs.

Ligand: The ligand component of this conjugate is AHPC, a small-molecule ligand that binds selectively to the VHL E3 ubiquitin ligase. Its stereochemistry is designed to optimize binding affinity and specificity, ensuring efficient recruitment of the E3 ligase to the target protein.

Reactive Site: The reactive site is the carboxylic acid group (-COOH) at the terminal end of the linker, which enables coupling with a target protein ligand through amide bond formation. Recommended reaction types include EDC/NHS-mediated coupling, which facilitates efficient and stable conjugation.

Recommended Target Protein Ligand: The ideal warhead for this molecule would be an amine-containing ligand that can form a stable amide bond with the carboxylic acid reactive site. This configuration ensures robust conjugation, enhancing the degradation efficiency of the target protein in experimental studies focused on elucidating protein function and interactions.